Susan M. Gasser

Nuclear organization in development and genome stability

Understanding the three- and four-dimensional coordination of biochemical and enzymatic events, i.e., in space and time, will help scientists render basic discoveries in molecular and cell biology, useful for medical purposes. The Gasser laboratory focuses on two lines of research that integrate analyses of spatial and temporal organization into molecular and genetic models of subcellular events. Our goal is to understand how chromosomal integrity is maintained, how cells ensure an accurate propagation of the genome, and how cells regulate the complex pattern of gene expression that occurs during tissue differentiation. We have established that genes are spatially organized - and reorganized - within the nucleus in a tissue-specific manner during C. elegans development. Nematode genetics provide an opportunity to screen for proteins and genes that establish this organization. Once these are identified, we can mutate selected components of the molecular machinery and monitor the developmental defects that arise from a perturbation of the spatial and/ or temporal organization of genes.

For studying the impact of subnuclear organization on DNA damage and repair, we use baker's yeast as our model organism. A combined genetic and biochemical approach allows us to explore how perturbation of genome organization provokes mutation or instability. This approach is validated by a class of degenerative human diseases, the laminopathies, in which mutations in a structural component of the nuclear envelope lead to myopathic degeneration or progeria. Genetics helps us bridge from human disease to our research model organisms, and allows us to dissect the redundant processes that fine-tune cellular events. We also exploit live-cell microscopy of fluorescently tagged molecules to monitor events with quantitative imaging, again allowing us to draw parallels between model organisms and human disease.